Cell adhesion molecules are a group of molecules existing on cellular surface and mediating the adhesion between a cell and a cell and between cell and extracellular matrix. The phenomenon called adhesion through adhesive molecules is involved not only in cell adhesion but also in cellular information transmission and activation, and plays an important role in biological defense reactions mainly including inflammation and immune reaction. Inflammatory leukocyte playing an important role in inflammation adheres to cell adhesion molecules expressed in vascular endothelium, and subsequently passes through in between vascular endothelial cells to infiltrate into an inner tissue. Then the inflammatory leukocyte releases various inflammatory mediators and the like, so that the leukocyte plays an important role in the onset and invasion of inflammation. Currently, the presence of various cell adhesion molecules is known. Among these, ICAM-1 (intercellular adhesion molecule-1) is significantly expressed in the vascular endothelium in which inflammation is caused. Therefore, it is suggested that ICAM-1 is highly involved therein (see, for example, non-patent reference 1).
As T cell receptors, CD4, CD8, and VCAM-1 (vascular cell adhesion molecule-1), ICAM-1 is a cell adhesion molecule belonging to the immunoglobulin super family, and is a protein of 76 to 114 kDa, which depends on the difference in the sugar chain added. ICAM-1 was considered as a ligand of LFA-1 (lymphocyte function-associated antigen-1) at an early stage (see, for example, non-patent references 2 and 3). Subsequently, it was revealed that the molecule worked as ligands of Mac-1 and CD43 (see, for example, non-patent references 4 and 5).
Examinations using various animal models indicate that a therapeutic treatment using anti-ICAM-1 antibodies is effective not only for rheumatoid arthritis (see, for example, non-patent references 6 and 7) but also for glomerular nephritis (see, for example, non-patent reference 8), rejections in organ grafting (see, for example, non-patent reference 9), pneumonia (see, for example, non-patent reference 10), myocardititis (see, for example, non-patent reference 11), asthma (see, for example non-patent, reference 12), and ulcer (see, for example, non-patent reference 13). Thus, it is suggested that there is a possibility that the therapeutic treatment of various diseases can be achieved by controlling the expression of ICAM-1.
Antisense and antibodies against ICAM-1 have been developed so far as therapeutic agents and immunosuppressive agents of rheumatoid and inflammatory diseases. However, none of such agents have been introduced on market yet. Therefore, creation of a novel therapeutic agent for inflammatory diseases with a novel activity mechanism has been desired.
It is reported that Coprophilin represented by the following formula (2) has an antibacterial activity. However, there has been no description about an activity of suppressing ICAM-1 expression, an anti-inflammatory activity, an immunosuppressive activity and an activity of suppressing cell growth (see, for example, non-patent reference 14).
Non-patent reference 1: Patarroyo M, et al.: Lancet., 1989, Nov. 11, 2(8672), 1139-42.Non-patent reference 2: Dustin M L, et al.: Annu. Rev. Immunol., 1991, 9, 27-66Non-patent reference 3: Springer T A: Nature, 1990, 346, 425-434Non-patent reference 4: Diamond M S, et al.: J. Cell Biol., 1990, 111, 3129-3139Non-patent reference 5: Rosenstein Y, et al.: Nature, 1991, 354, 233-235Non-patent reference 6: Iigo Y, et al.: J. Immunol., 1991, 147, 4167-4171Non-patent reference 7: Kavanaugh A F, et al.: Arthritis. Rheum., 1992, 35(Sppul.), 53Non-patent reference 8: Kawasaki K, et al.: J. Immunol., 1993, 150, 1074-1083Non-patent reference 9: Cosimi A B, et al.: J. Immunol., 1990, 144, 4604-4612Non-patent reference 10: Barton R W, et al.: J. Immunol., 1989, 143, 1278-1282Non-patent reference 11: Seko Y, et al.: J. Clin. Invest., 1993, 91, 1327-1336Non-patent reference 12: Wegner C D, et al.: Science, 1990, 247, 456-459Non-patent reference 13: Wallance J L, et al.: Am. J. Physiol., 1993, 265, G933-998Non-patent reference 14: Ondeyka J G, et al.: Bioorg. Med. Chem. Lett., 1998, 8, 3439-3442